Vortioxetine and Lewy Body Disorders - Charles M. Lepkowsky, Ph.D - irjpms

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International Research Journal of Pharmacy and Medical Sciences
                                                                                                                     ISSN (Online): 2581-3277

                   Vortioxetine and Lewy Body Disorders
                                                Charles M. Lepkowsky, Ph.D.
                                 Independent Practice, 1143 Deer Trail Lane, Solvang, CA USA 93463
                                                      Telephone: (805) 688-1229
                                                   Email: clepkowsky @ gmail.com

Abstract—
Introduction: Vortioxetine is a newer antidepressant medication with reported potential for mitigating cognitive impairment secondary to major
depressive disorder. However, the current study suggests that the use of Vortioxetine for patients with Lewy Body Disorders may present
complications due to its interactions with medications frequently prescribed to that population, including Bupropion and Carbidopa-Levodopa.
Methods: A case study is presented to illustrate Vortioxetine’s potential interactions with Lewy pathology and other medications frequently used
for patients with Lewy Body Disorders. Vortioxetine’s potential for exacerbation of Lewy pathology symptoms including cognitive impairment
and gastric immotility is described, and the underlying biochemical mechanisms are explained.
Results: The use of Vortioxetine exacerbated Lewy Body symptoms including cognitive impairment and gastric immotility. Discontinuation of
Vortioxetine alleviated symptom exacerbation.
Discussion and Conclusions: The chemical mechanisms responsible for symptom changes consequent to Vortioxetine’s interactions with
serotonergic and cholinergic suppression characteristic of Lewy pathology, and other medications used for the Lewy Body patient in the case
study are discussed. The use of Vortioxetine for patients with Lewy Body Disorders may present complications due to its effect on
neurotransmitter pathways affected by Lewy pathology, as well as its interactions with medications frequently prescribed to that population.
Recommendations are made for screening Lewy Body patients before prescribing Vortioxetine.

Keywords— Cognitive Impairment; Constipation; Drug Interactions; Lewy Body Disorders; Parkinson’s Disease; Vortioxetine.

                                                                           other conditions wherein cognitive impairment is a prominent
                        I.    INTRODUCTION                                 feature [41], prompting the FDA to update Vortioxetine labels
                                                                           to ―include data showing improvement in processing speed, an

   A        pproved for use in the U.S. by the FDA in 2013 [1,
            2], Vortioxetine is described as both an atypical
            antipsychotic and an antidepressant. Intended for
the treatment of major depressive disorder (MDD) [3], it may
                                                                           important aspect of cognitive function in acute Major
                                                                           Depressive Disorder (MDD)‖ [5].
                                                                           C. Mechanisms of Action
have benefit for reduction of anxiety [4] and enhancement of
memory and cognitive performance [5]. The purpose of this                      Vortioxetine’s mechanism of action is novel, and more
paper is to review the literature on Vortioxetine’s efficacy for           complex than that of other antidepressants [42]. Vortioxetine
treating MDD and anxiety, potential for memory                             is metabolized by cytochrome P450 enzymes (e.g., CYP450
enhancement, mechanisms of action, and specific suitability                2D6)      and     subsequently     by    uridine     diphosphate
for use with patients diagnosed with Lewy Body disorders.                  glucuronosyltransferase [43]. Although its direct mechanism
                                                                           of action is not fully understood, Vortioxetine is thought to act
A. Clinical Trials, Efficacy and Safety, Long-Term Use                     as a serotonin reuptake inhibitor (SRI), and is classified as a
    In clinical trials, Vortioxetine has demonstrated efficacy in          serotonin modulator and simulator (SMS). Acting as a partial
reducing the symptoms of depression [4, 6-18] and anxiety [4,              agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and an
19, 20], comparing favorably with SNRI’s including                         antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors,
Duloxetine [17, 20-23], Venlafaxine [24], and Desvenlafaxine               Vortioxetine is a serotonin (5-HT) transporter (SERT)
[25], atypical antidepressants including Agomelatine [26, 27],             inhibitor [44-48].
and SRI’s including Escitalopram, Sertraline, and Vilazodone                   Achieving significant clinical effects at much lower
[25] for efficacy and safety. Vortioxetine appears to compare              serotonin SERT occupancy (inhibition) rates than traditional
favorably with SRIs including Paroxetine for mitigation of                 SERT inhibitors, Vortioxetine (unlike SRIs) appears to engage
sleep disturbance [28, 29], and may have long-term benefit in              additional downstream and non-serotonergic mechanisms that
the treatment of MDD [30, 31].                                             mediate its antidepressant and domain-specific effects on
                                                                           cognition [49]. Its interaction with 5-HT-receptor-mediated
B. Memory Enhancement                                                      negative feedback mechanisms controlling neuronal activity
   Animal research indicates that Vortioxetine enhances                    increases     serotonergic,    noradrenergic,     dopaminergic,
memory [32], restoring reversal learning [33], increasing                  cholinergic,        histaminergic       and        glutamatergic
hippocampal synaptic plasticity [34], and improving                        neurotransmission in brain structures associated with MDD,
recognition memory [35], benefits not found with Fluoxetine                its specific antagonism of 5-HT3 receptors reducing 5-HT3
[36], Escitalopram, or Duloxetine [37]. Clinical trials with               receptor-mediated excitation of GABA interneurons,
human subjects diagnosed with MDD indicate that                            consequently increasing hippocampal pyramidal activity [50].
Vortioxetine not only mitigates cognitive impairment as a                  The downstream mechanisms influencing glutamatergic and
symptom of MDD [37-40], but may improve cognition in

                                                                      12

  Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
  (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
International Research Journal of Pharmacy and Medical Sciences
                                                                                                                ISSN (Online): 2581-3277

GABAergic neurotransmission are thought to be the basis of                  α‐synucleinopathy most infamously impairs dopaminergic
Vortioxetine’s memory- and cognition-enhancing effects [51-             function producing Parkinsonian symptoms, but can affect all
53].                                                                    neurotransmitter pathways [60, 61]. In LBDs, the emergence
                                                                        of MDD is associated with impairment of multiple
D. Drug Interactions
                                                                        neurotransmitter pathways, including serotonergic and
    Vortioxetine’s numerous and complex mechanisms of                   noradrenergic pathways [74-76], at a significantly higher rate
action create the potential for complications. Its 5-HT3                than in Alzheimer’s Disease [77]. NCDLB and PD are also
receptor antagonism appears to exert inhibitory effects over            characterized by cholinergic neural deficits and functional
the release of norepinephrine (NE) and acetylcholine (ACh)              impairment [60, 61, 69-83], which are recognized as
[54], complicating its role in the regulation of mood and               symptomatic features of α‐synucleinopathy [73, 83-85]. These
memory. Although Vortioxetine was initially thought to have             include motor symptoms, gait dysfunction, dyskinesias,
a relatively low risk for pharmacodynamic drug interactions             cognitive deterioration, psychosis, sleep abnormalities,
[50, 55], Vortioxetine peak plasma concentration and systemic           autonomic dysfunction, altered olfactory function [86], and
exposure are significantly decreased when Vortioxetine is co-           gastric immotility [87, 88].
administered with Rifampicin, a broad cytochrome P450
inducer which accelerates that enzyme’s metabolism of                   G. Gastric Immobility as a Quantifiable Indicator of
Vortioxetine [56].                                                      α‐synuclein Cholinergic Impairment
    Conversely, several CYP450 2D6 inhibitors (which limit                  Gastric immotility in Lewy Body patients is at least three
CYP450 2D6’s metabolism of Vortioxetine) significantly                  times as prevalent as it is among the general population [89],
increase Vortioxetine peak plasma concentration and systemic            and might be as a universal feature of Lewy Body disorders
exposure. These include Fluconazole, Ketoconazole,                      [90]. In both PD and NCDLB, α‐synuclein pathology is found
Bupropion, Cinacalcet, Fluoxetine, Paroxetine, Quinidine,               in the enteric nervous system [91-103], specifically in the
Ritonavir, and Terbinafine [43, 56]. Because Fluoxetine and             myenteric plexus (MP) [71, 72, 104-108] and the colonic
Paroxetine are selective serotonin reuptake inhibitors, additive        submucosal plexus (CSMP) [98], which is innervated by the
serotonergic effects with Vortioxetine specifically increase the        MP. The MP controls motility of the colon, and 95% of its
risk of serotonin syndrome [57]. Vortioxetine peak plasma               innervation is cholinergic [109], indicating that constipation in
concentration and systemic exposure are even greater in                 NCDLB and PD is the direct consequence of Lewy pathology
combination with the potent CYP450 2D6 inhibitor Bupropion              in the MP. The presence of α‐synuclein aggregates in the MP
[43]. When co-administered, Levodopa-Carbidopa (Sinemet)                and its symptomatic manifestation as constipation predate
also significantly increases Vortioxetine peak plasma                   cognitive and motor symptoms of Lewy body diseases [101,
concentration and systemic exposure [58, 59].                           108] so consistently that it has been nominated as a potential
    E. Lewy Body Disorders: Prevalence                                  biomarker for Lewy pathology [110]. Constipation is of
    Lewy body disorders are gaining prominence in the                   particular interest because it is the symptom of cholinergic
research literature, as their diagnostic criteria become more           impairment most immediately apparent to the patient and care
defined, making more apparent their increasing prevalence               givers [70], and frequency of bowel movements is a
[60, 61]. In 2017, 50 million people worldwide were                     quantifiable indicator of cholinergic impairment in Lewy body
diagnosed with neurocognitive disease, a figure expected to             patients [111].
exceed 75 million by 2030, and 131.5 million by 2050 [62-
64]. Approximately 22% of these diagnoses are assigned to               H. Medications Used to Treat Lewy Body Patients
Neurocognitive Disorder with Lewy Bodies (NCDLB)                            The importance of pharmacological facilitation of
(previously called Lewy Body Dementia) and 9% to                        serotonergic and dopaminergic systems to address motor and
Parkinson’s disease (PD) [65]. The prevalence of Lewy Body              depressive symptoms impaired by α‐synucleinopathy is well
disorders (LBDs) is expected to increase from 15.5 million              documented [112, 113]. Antidepressants with evidence-based
people worldwide today to over 40 million by year 2050 [64,             application for treating depression in LBD patients include the
66-67]. These figures are likely to grow, as more accurate              tricyclics Amitriptyline, Nortriptyline, and Desipramine,
diagnosis decreases the frequent misdiagnosis of LBDs [68].             which may be contraindicated due to their anticholinergic
                                                                        characteristics, SRIs including Citalopram, Sertraline,
F. α‐synucleinopathy                                                    Paroxetine, and Fluoxetine, SNRIs including Venlafaxine, and
    Both PD and NCDLB are characterized by the                          the atypical antidepressant Bupropion [114-117].
intraneuronal presence of Lewy bodies, pathologic aggregates                In order to preserve gait, balance, and other basic motor
of    the     synaptic   protein    α‐synuclein   [69,   70].           functions, Lewy body patients with significant Parkinsonian
α‐synucleinopathy is not confined to the central nervous                features are often prescribed L-dopa agents like Carbidopa-
system (CNS), but also affects the autonomic nervous system             Levodopa (branded as Sinemet or Stalevo). [70, 118, 119].
(ANS), the peripheral nervous system (PNS) and the enteric              ENS α‐synucleinopathy can be complicated or exacerbated by
nervous system (ENS), spreading from one nervous system                 Carbidopa-Levodopa, whose potential side effects include
area to another over time [71, 72]. Lewy bodies aggregate not           constipation [120-123]. Anticholinergic agents including
only near the nucleus of the neuron, but even more abundantly           Trihexyphenidyl (branded as Artane or Trihex) and
in neurites (axons and dendrites) [73].                                 Benztropine mesylate (branded as Cogentin) prescribed to

                                                                   13

 Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
 (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
International Research Journal of Pharmacy and Medical Sciences
                                                                                                                ISSN (Online): 2581-3277

reduce resting tremor in Lewy body patients can also                    suppression, whose symptomatic expression paradoxically
exacerbate gastric immotility through cholinergic suppression           includes cognitive deterioration, as well as motor and gait
in the ENS. [119, 124-126].                                             dysfunction, dyskinesias, psychosis, sleep abnormalities,
                                                                        altered olfactory function [86], and autonomic dysfunction,
I. Medications Used to Treat Cholinergic Impairments in
                                                                        including gastric immotility [87, 88]. Gastric immotility’s
Lewy Body Patients
                                                                        advancement from constipation to obstipation and impaction
    Cholinergic agonists like acetylcholinesterase inhibitors           complicate treatment by interfering with mobility, sleep,
(AChEIs) are often used for symptomatic relief of cholinergic           cognition, and mood, increase the cost of care, and can
impairment attributable to α‐synuclein pathology [74, 86, 127-          debilitate and/or dramatically reduce the quality of life for the
129]. For the treatment of LBD cognitive impairment, the                patient [143-149]. Exacerbation of α‐synuclein cholinergic
cholinergic agonist Donepezil (Aricept) compares favorably              suppression consequent to the use of Vortioxetine in
with other AChEIs including Galantamine and Rivastigmine,               combination with Bupropion is illustrated in the following
improving cognition [130], but with fewer side effects [131].           case study, for which an Institutional Review Board has
Significant improvements in cognition and behavior following            granted a waiver.
administration of Donepezil disappear when Donepezil is
withdrawn, and return when Donepezil is readministered                                           II.   METHODS
[132]. In a 52-week study, long-term cognitive improvement                  For the purpose of illustrating potential interactions
was maintained in LBD patients with regular use of                      between Vortioxetine and other medications frequently used to
Donepezil, with no increase in Parkinsonian features or other           treat patients diagnosed with Lewy Body disorders, a case
clinically significant events. [133, 134].                              study was selected using pre-existing deidentified records
    Other symptoms of α‐synuclein cholinergic impairment                originally collected for clinical purposes.
including hallucinations, delusions, and psychotic symptoms
in PD patients have been reduced using Donepezil, without the           A. Case Study
emergence of other side effects or exacerbation of                          Mr. C. was a white male between 65 and 70 years of age
Parkinsonian features [135, 136]. Donepezil’s efficacy for              diagnosed with Neurocognitive Disorder with Lewy Bodies
consistent reduction of neurocognitive symptoms in PD &                 (NCDLB). His symptoms were characteristic of Lewy Body
NCDLB without exacerbation of Parkinsonian features or                  α-synucleinopathy, including late-life onset major depressive
other side effects has been confirmed by a Cochrane database            disorder (MDD), anxiety, motor abnormalities (tremor,
systematic review of previous research [137] and reproduced             weakness), gait dysfunction, dyskinesias, cognitive
in subsequent research [138, 139]. Donepezil’s support of               deterioration including short-term memory loss and difficulty
cholinergic neurotransmitter pathways to counter alpha-                 word-finding, sleep abnormalities including REM Sleep
synuclein cholinergic impairment in the MP and the CSMP                 Behavior Disorder (RSBD) and REM Sleep without Atonia
reducs constipation in LBD patients, without exacerbation or            (RSWA), and autonomic dysfunction including appetite
instigation of other symptoms [111]. Longitudinal case studies          suppression and gastric immotility, which had progressed over
indicate that these benefits endure over 6, 12, and 18 month            the preceding two years from constipation to obstipation to
periods [140, 141, 142].                                                impaction. His frequency of bowel movements was about once
                                                                        a week, with periodic decreases infrequency. He had been
J. Vortioxetine and LBD Patients
                                                                        hospitalized three times during the previous year for treatment
    Frequently prescribed to LBD patient for containment of             of impaction. Screening using the Mini-Mental State Exam
Parkinsonian features, Levodopa-Carbidopa (Sinemet)                     (MMSE) [150], the Quick Dementia Rating Scale (QDRS)
significantly increases Vortioxetine peak plasma concentration          [151], and the Lewy Body Composite Risk Score (LBCRS)
and systemic exposure, requiring significant reductions of              [152] indicated mild cognitive impairment (MCI) and
Vortioxetine dosages and close monitoring [58, 59]. Often               neurocognitive impairment consistent with Lewy body
prescribed to LBD patients for management of MDD                        diseases.
symptoms, the SRI’s Fluoxetine and Paroxetine are CYP450                    The patient’s medication regimen included Bupropion 75
2D6 inhibitors, which co-administered with Vortioxetine can             mg HS, 50 mg QHS, Clonazepam 0.325 mg QHS,
produce additive serotonergic effects with the risk of serotonin        Aripiprazole 5 mg QHS, Melatonin 6 mg QHS PRN,
syndrome [43, 56]. Also used to treat depression in LCDs,               Mirtazapine 30 mg QHS, Carbidopa-Levodopa 25/100 mg
Bupropion is a potent CYP450 2D6 inhibitor, and co-                     TID, Memantine 10 mg BID. Bupropion and Aripiprazole had
administered with Vortioxetine can more than double its peak            been prescribed to address the MDD; Clonazepam for anxiety;
plasma concentration and systemic exposure [56, 57].                    Melatonin and Mirtazapine for sleep assistance, with the
Frequently used to address sleep impairment in LBD patients,            intention that Mirtazepine might also mitigate the MDD;
tricyclic      antidepressants     multiply       Vortioxetine’s        Memantine for cognitive impairment; and Carbidopa-
anticholinergic effects [53], demonstrated with Amitriptyline,          Levodopa for gait disturbance and other motor symptoms.
Nortriptyline, and Desipramine [73].                                        The prescriptions appeared to improve mood, motor
    In LBD patients, amplified cholinergic suppression                  function, and cognitive function, but there was no change in
consequent to the use of Vortioxetine in combination with               RSBD/RSWA or the frequency of bowel movements. To
tricyclics or Bupropion can exacerbate α‐synuclein cholinergic          address the symptom of constipation and possibly further

                                                                   14

 Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
 (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
International Research Journal of Pharmacy and Medical Sciences
                                                                                                               ISSN (Online): 2581-3277

improve cognitive functioning, the patient was prescribed              apparently exacerbating Lewy Body α‐ synuclein cholinergic
Donepezil 2.5 mg daily. Within two weeks, the frequency of             suppression in the ENS.
bowel movements had increased to every other day. The                      Although believed to bind in the same binding site,
patient stated dissatisfaction with his bowel production and           Vortioxetine’s serotonergic inhibitory mechanism varies from
appetite, so the dosage of Donepezil was increased to 5 mg             classical 5-HT3 receptor competitive antagonists. After partial
daily, and four weeks later to 10 mg daily, with subsequent            agonist activity, Vortioxetine demonstrates what has been
improvements in appetite, intake, and bowel output volume.             described as ―a persistent and insurmountable inhibition‖
The patient’s frequency of bowel movements increased to                [153]. The molecular mechanisms underlying Vortioxetine’s
once a day, without increasing Parkinsonian features or other          site binding appear to be different from currently known 5-
clinically significant symptoms. The patient and his spouse            HT3Aorthosteric ligands. In addition to binding in a manner
reported concurrent significant improvement in short-term              that resemble the setron class of competitive antagonists and
memory, word finding, and general cognitive functioning.               5-HT, interacting with residues of the aromatic box motif in
Retesting with the MMSE, the QDRS and the LBCRS verified               the orthosteric binding site, Vortioxetine additionally interacts
these reports. These results remained stable when reassessed at        with residues not previously described to be important for the
intervals of 6, 12, and 18 months [140, 141, 142].                     binding of either setrons or 5-HT, including Thr176 on loop B
    18 months after initiation of treatment with Donepezil, the        and Val202 on loop F [153]. As Vortioxetine’s peak plasma
patient stated increased depression, and (in addition to other         concentration and systemic exposure can be more than
medications reported above) was prescribed Vortioxetine 10             doubled by its combined interactions with Bupropion and
mg daily. Within two weeks, the patient reported that the              Levodopa-Carbidopa [43, 58, 59], its serotonergic inhibitory
frequency of bowel movements had dropped to once a week or             potential is also significantly increased. In the case study, it
less. He was taken to the Emergency Room at the hospital and           appears that the combination of Vortioxetine’s serotonergic
was treated for impaction after 10 days without a bowel                and cholinergic inhibition significantly interfered with
movement. The patient also complained of increased cognitive           cognition.
impairment (confusion, difficulty with calculations, task                  Vortioxetine also has potential for interaction with other
completion, and word-finding). Discussion with the                     antidepressants with evidence-based application for treating
prescribers led to a consensus that the dramatic reductions in         depression in LBD patients. These include the tricyclics
cognitive function and gastric motility manifested as reduction        Amitriptyline, Nortriptyline, and Desipramine, SRIs including
in frequency of bowel movements were likely the result,                Citalopram, Sertraline, Paroxetine, and Fluoxetine, SNRIs
respectively, of serotonergic inhibition, and exacerbation of          including Venlafaxine, and the atypical antidepressant
α‐ synuclein cholinergic suppression consequent to the use of          Bupropion [114-117]. Fluoxetine and Paroxetine are potent
Vortioxetine in combination with Bupropion and Levodopa-               CYP450 2D6 inhibitors, and Fluoxetine’s inhibitory effects on
Carbidopa. The use of Vortioxetine was discontinued,                   CYP-activity can persist for several weeks after fluoxetine
although the use of Bupropion and other medications                    discontinuation because of the long half-life of fluoxetine and
continued.                                                             its metabolite Norfluoxetine, which similar to Sertraline is a
                                                                       moderate CYP2D6 inhibitor [154]. CYP450 2D6 inhibition
                        III.   RESULTS                                 lends these medications potential for increasing the peak
    The patient reported that about 24 following                       plasma concentration and systemic exposure of Vortioxetine,
discontinuation of Vortioxetine, gastric motility had resumed,         increasing not only Vortioxetine’s potential for cholinergic
with a bowel movement. Within 48 hours, the frequency of               suppression, but also increasing the risk of serotonin syndrome
bowel movements returned to once daily, and the patient and            when it is co-administered with SRI’s and SNRI’s. The
his spouse reported a return to pre-Vortioxetine levels of             tricyclics Amitriptyline, Nortriptyline, and Desipramine have
cognitive functioning. There were no other changes in the              anticholinergic side effects, which can also potentiate
patient’s symptoms. The patient’s symptom picture has                  Vortioxetine’s potential for cholinergic suppression when co-
remained constant during the six months since the                      administered with Vortioxetine.
discontinuation of Vortioxetine.                                           The drug interactions described above and illustrated in the
                                                                       case study suggest that the use of Vortioxetine with LBD
             IV.   DISCUSSION AND CONCLUSIONS                          patients might present complications, if not risks. There are
    The case study serves as a quantifiable demonstration of           numerous other prescriptive and over the counter (OTC)
Vortioxetine’s potential for serotonergic and cholinergic              medications with anticholinergic effects frequently used by
inhibition, and importantly, its reversibility. As a potent            this population, including but not limited to Alimemazine
CYP450 2D6 inhibitor, Bupropion interferes with the                    (Theralen), Amantadine (Symmetrel), Alverine (Spasmonal),
metabolism of Vortioxetine, resulting in significant increases         Belladona (Multiple), Amoxapine (Asendin), Alprazolam
in Vortioxetine peak plasma concentration and systemic                 (Xanax), Aripiprazole (Abilify), Asenapine (Saphris),
exposure [43]. Levodopa-Carbidopa also significantly                   Carbamazepine (Tegretol), Atropine (Sal-Tropine), Atenolol
increases Vortioxetine peak plasma concentration and                   (Tenormin),      Cyclobenzaprine      (Flexeril),   Benztropine
systemic exposure [58, 59]. As illustrated by the case study,          (Cogentin),      Brompheniramine         maleate      (Bromax),
the combined interaction of Bupropion and Levodopa-                    Cyproheptadine (Periactin), Brompheniramine (Dimetapp),
Carbidopa with Vortioxetine can be dramatic, in this instance          Carbinoxamine (Histex, Carbihist), Captopril (Capoten),

                                                                  15

 Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
 (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
International Research Journal of Pharmacy and Medical Sciences
                                                                                                                   ISSN (Online): 2581-3277

Cetirizine (Zyrtec), Chlorpheniramine (Chlor-Trimeton),                    necessary before stronger conclusions can be drawn about the
Chlorthalidone       (Diuril,      Hygroton),     Chlorpromazine           appropriateness of Vortioxetine for specific populations.
(Thorazine), Cimetidine (Tagamet), Clemastine (Tavist),
Clidinium (Librax), Clomipramine (Anafranil), Clorazepate                                      LIST OF ABBREVIATIONS
(Tranxene), Clozapine (Clozaril), Codeine (Contin),                        Major depressive disorder (MDD)
Colchicine (Colcrys), Darifenacin (Enablex), Desloratadine                 Serotonin Reuptake inhibitor (SRI)
(Clarinex), Dicyclomine (Bentyl), Diazepam (Valium),                       Serotonin and Norepinephrine Reuptake inhibitor (SNRI)
Dimenhydrinate         (Dramamine),       Digoxin       (Lanoxin),         Food and Drug Administration (FDA)
                                                                           Cytochrome P450 enzymes (e.g., CYP450)
Diphenhydramine (Benadryl), Dipyridamole (Persantine),
                                                                           Serotonin modulator and simulator (SMS)
Doxepin (Sinequan), Doxylamine (Unisom), Disopyramide                      Five Hydroxy-Tryptophan (5-HT)
phosphate (Norpace), Fentanyl (Duragesic, Actiq),                          Serotonin (5-HT) transporter (SERT)
Fesoterodine (Toviaz), Flavoxate (Urispas), Fluvoxamine                    Gamma Amino Butyric Acid (GABA)
(Luvox), Furosemide (Lasix), Haloperidol (Haldol),                         Norepinephrine (NE)
Hydralazine (Apresoline), Hydrocortisone (Cortef, Cortaid),                Acetylcholine (ACh)
Hydroxyzine (Atarax, Vistaril), Hyoscyamine (Anaspaz,                      Acetylcholinesterase (AChE)
Levsin), Iloperidone (Fanapt), Imipramine (Tofranil),                      Acetylcholinesterase inhibitor (AChEI)
Isosorbide (Isordil, Ismo), Loperamide (Immodium),                         Neurocognitive Disorder with Lewy Bodies (NCDLB)
                                                                           Parkinson’s disease (PD)
Loratadine (Claritin), Loxapine (Loxitane), Meclizine
                                                                           Lewy Body disorders (LBDs)
(Antivert), Meperidine (Demerol), Methocarbamol (Robaxin),                 Central nervous system (CNS)
Methotrimeprazine (Levoprome), Metoprolol (Lopressor,                      Autonomic nervous system (ANS)
Toprol), Molindone (Moban), Morphine (Contin, Avinza),                     Peripheral nervous system (PNS)
Nefopam (Nefogesic), Nifedipine (Procardia, Adalat),                       Enteric nervous system (ENS)
Oxcarbazepine         (Trileptal),     Olanzapine       (Zyprexa),         Myenteric plexus (MP)
Orphenadrine (Norflex), Oxybutynin (Ditropan), Perphenazine                Colonic submucosal plexus (CSMP)
(Trilafon), Pimozide (Orap), Prednisone (Deltasone,                        Rapid Eye Movement (REM)
Sterapred), Procyclidine (Kemadrin), Promazine (Sparine),                  REM Sleep Behavior Disorder (RSBD)
                                                                           REM Sleep without Atonia (RSWA)
Promethazine (Phenergan), Propentheline (Pro-Banthine),
                                                                           Mini-Mental State Exam (MMSE)
Propiverine (Detrunorm), Quetiapine (Seroquel), Quinidine                  Quick Dementia Rating Scale (QDRS)
(Quinaglute), Ranitidine (Zantac), Risperidone (Risperdal),                Lewy Body Composite Risk Score (LBCRS)
Scopolamine (Transderm Scop), Solifenacin (Vesicare),
Theophylline (Theodur, Uniphyl), Thioridazine (Mellaril),                                          DECLARATIONS
Tolterodine (Detrol), Trazodone (Desyrel), Triamterene                     Ethics approval and consent to participate: The Santa Barbara
(Dyrenium), Trifluoperazine (Stelazine), Trihexyphenidyl                   Cottage Hospital Institutional Review Board granted a waiver
(Artane), Trimipramine (Surmontil), Trospium (Sactura), and                (##18-81ix) for this case study.
Warfarin (Coumadin) [119]. By no means exhaustive, this list               Consent for publication: A completed consent for publication
gives some idea of the broad range of prescriptive and non-                form for the case study is on file with the author.
prescriptive medications with potential to interact with                   Availability of data and materials: Data sharing is not
Vortioxetine to suppress cholinergic function. Because many                applicable to this article as no datasets were generated or
of these medications are non-prescriptive, the possibility that            analyzed during the current study.
prescribers might be unaware of their use increases the risk of            Competing interests: There are no competing interests
potential interaction with Vortioxetine.                                   involved in the research reported or the writing of this paper.
    Complicating the prescription picture, LBD patients are                Funding: This research received no specific grant from any
often simultaneously medicated by an internist, a psychiatrist,            funding agency in the public, commercial or not-for-profit
a neurologist, a movement specialist, and possibly other                   sectors.
specialists (e.g., gastroenterologist, urologist). [70]. Difficulty        Authors' contributions: This paper was written according to
coordinating ongoing communication between prescribers in                  the Ethical Principles of the American Psychological
siloed care settings creates greater potential risk for dangerous          Association. Charles M. Lepkowsky, Ph.D. is the sole author
drug interactions [155, 156]. At this time, it appears that the            of this work, including its conception and design; the
use of Vortioxetine for patients diagnosed with Lewy Body                  acquisition, analysis, and interpretation of data; drafting,
disorders might present numerous risks. However,                           writing, and editing; final approval of the version published;
Vortioxetine is a relatively new medication, and as indicated              and accepts accountability for all aspects of the work in
above, research to date has produced results that are not                  ensuring that questions related to the accuracy or integrity of
entirely consistent. Risks can be mitigated by ongoing close               any part of the work are appropriately investigated and
communication between prescribers, which is recommended                    resolved.
for the use of Vortioxetine, as well as any other medication for           Acknowledgements: There are no acknowledgements pertinent
LBD patients. Further research with larger data sets matching              to this case study.
groups for diagnosis, age, gender, and other variables will be

                                                                      16

 Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
 (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
International Research Journal of Pharmacy and Medical Sciences
                                                                                                                                        ISSN (Online): 2581-3277

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  Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
  (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
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  (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
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  Charles M. Lepkowsky, ―Vortioxetine and Lewy Body Disorders,‖ International Research Journal of Pharmacy and Medical Sciences
  (IRJPMS), Volume 2, Issue 2, pp. 12-20, 2019.
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